This invention relates to a water soluble lactic acid addition salt of (-)-(2R)- cis!-4-4-4-4--5-(2,4-difluorophenyl)-tetrahydro-5-(1 H-1 ,2,4-triazol-1 -ylmethyl)-3-furanyl!methoxy!phenyl!-1 -piperazinyl!phenyl!-2,4-dihydro-2-1 (S)-ethyl-2(S)-hydroxpropyl!-3H-1,2,4-triazol-3-one, pharmaceutical compositions containing the lactic acid addition salt in pharmaceutically acceptable carrier such as aqueous lactic acid as well as methods of treating and/or preventing susceptible fungal infections in a host including mammals especially humans with said lactic acid addition salt.
Systemic fungal infections are becoming a serious and potentially fatal problem in immunocompromised patients. Such patients have a compromised or suppressed immune system due to immunosuppression therapy following organ transplant, use of cytotoxic drugs for treatment of cancer or HIV infections. Injectable antifungal agents such as Amphotericin B are active against a wide variety of fungi but exhibit significant toxic side effects. The azole antifungals fluconazole, itraconazole and ketoconazole can be administered orally or via injection but have more limited antifungal activity th an Amphotericin B. In addition, prolonged exposure to antifungals agents has resulted in increased fungal resistance to some of these agents.
Thus, there is a need for a broad spectrum antifungal agent having activity against fungi such as Aspergillus and Candida krusei resistant to existing anti- fungal agents and which is capable of being administered intravenously.
International Publication No. PCT/EP/00174, published 27 Jul. 1995 discloses azole tetrahydrofuran and dioxolane antifungals, but not the lactic acid addition salt of this invention.
International Publication No. WO 95/17407 published 29 Jun. 1995 discloses various (2 R-cis)-4-4-4-4--5-(2,4-difluorophenyl)-tetrahydro-5-(1 H-1,2,4-triazol-1 -ylmethyl)-3-furanyl!methoxy!phenyl!-1 -piperazinyl!phenyl!2,4-dihydro-2-mono- or dihydroxy(C.sub.3 -C.sub.8) alkyl!-3 H-1,2,4-triazol-3-one substituted antifungals, esters, ethers and salts thereof. The hydrochloride salt of the glycine ester of (-)-(2 R)-cis!-4-4-4-4--5-(2,4-difluorophenyl)-tetrahydro-5-(1 H-1,2,4-triazol-1 -ylmethyl)-3-furanyl!methoxy!phenyl!-1 -piperazinyl!phenyl!-2,4-dihydro-2-1 (S)-ethyl-2(S)-hydroxypropyl!-3 H-1,2,4-triazol-3-one is disclosed in U.S. Pat. No. 5,714,490. There is no disclosure in the above-listed patent or patent applications of the specific monolactic acid addition salt or the specific pharmaceutical compositions of the present invention.